Karen Steinhoff

Positron-emission tomography imaging in the diagnosis of bisphosphonate-related osteonecrosis of the jaw

OBJECTIVES The purpose of this study was to investigate the sensitivity of F-18 fluoride and F-18 fluorodeoxyglucose (FDG) positron-emission tomography (PET) in the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ), and to test their suitability for assessing the severity of BRONJ. STUDY DESIGN Nine patients with BRONJ were studied using F-18 fluoride and F-18 FDG PET. For analysis, 8 regions of interest (ROI) were defined in the jaws of each patient. Maximum count rates for each ROI in both PET examinations were analyzed. RESULTS In both studies, increased tracer enhancement was observed in regions with BRONJ. Uptake of fluoride significantly exceeded that of FDG. FDG uptake increased systematically, but not significantly, with increasing severity of BRONJ. CONCLUSION F-18 fluoride PET is a sensitive method for diagnosis of BRONJ. FDG PET could be useful for evaluation of the severity of BRONJ. Further studies are required to prove the specificity of the methods.

Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice

The present study aimed to determine the effect of thyroid hormone dysfunction on brown adipose tissue activity and white adipose tissue browning in mice. Twenty randomized female C57BL/6NTac mice per treatment group housed at room temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal 18F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivo14C-acetate loading assay and assessment of thermogenic gene and protein expression permitted analysis of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and hypothyroid mice. 18F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced 18F-FDG uptake. In white adipose tissue of both, hyper- and hypothyroid mice, we found a significant induction of thermogenic genes together with multilocular adipocytes expressing UCP1. Taken together, these results suggest that both the hyperthyroid and hypothyroid state stimulate WAT thermogenesis most likely as a consequence of enhanced adrenergic signaling or compensation for impaired BAT function, respectively.

A novel thermoregulatory role for PDE10A in mouse and human adipocytes

Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small‐animal PET/MRI and the novel radioligand [18F]‐AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP‐10 recruited BAT and potentiated thermogenesis in vivo. In diet‐induced obese mice, chronic administration of MP‐10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP‐10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes.

CT-based attenuation correction in I-123-ioflupane SPECT.

Purpose Attenuation correction (AC) based on low-dose computed tomography (CT) could be more accurate in brain single-photon emission computed tomography (SPECT) than the widely used Chang method, and, therefore, has the potential to improve both semi-quantitative analysis and visual image interpretation. The present study evaluated CT-based AC for dopamine transporter SPECT with I-123-ioflupane. Materials and methods Sixty-two consecutive patients in whom I-123-ioflupane SPECT including low-dose CT had been performed were recruited retrospectively at 3 centres. For each patient, 3 different SPECT images were reconstructed: without AC, with Chang AC and with CT-based AC. Distribution volume ratio (DVR) images were obtained by scaling voxel intensities using the whole brain without striata as reference. For assessing the impact of AC on semi-quantitative analysis, specific-to-background ratios (SBR) in caudate and putamen were obtained by fully automated SPM8-based region of interest (ROI) analysis and tested for their diagnostic power using receiver-operator-characteristic (ROC) analysis. For assessing the impact of AC on visual image reading, screenshots of stereotactically normalized DVR images presented in randomized order were interpreted independently by two raters at each centre. Results CT-based AC resulted in intermediate SBRs about half way between no AC and Chang. Maximum area under the ROC curve was achieved by the putamen SBR, with negligible impact of AC (0.924, 0.935 and 0.938 for no, CT-based and Chang AC). Diagnostic accuracy of visual interpretation also did not depend on AC. Conclusions The impact of CT-based versus Chang AC on the interpretation of I-123-ioflupane SPECT is negligible. Therefore, CT-based AC cannot be recommended for routine use in clinical patient care, not least because of the additional radiation exposure.

The Effects of Thyroid Hormones on Gene Expression of Acyl-Coenzyme A Thioesterases in Adipose Tissue and Liver of Mice

Background: Thyroid hormones (TH) exert pleiotropic effects on glucose and lipid homeostasis. However, it is as yet unclear how TH regulate lipid storage and utilization in order to adapt to metabolic needs. Acyl-CoA thioesterases (ACOTs) have been proposed to play a regulatory role in the metabolism of fatty acids. Objectives: We investigated the interaction between thyroid dysfunction and Acot expression in adipose tissues and livers of thyrotoxic and hypothyroid mice. Methods: Ten-week-old female C57BL/6NTac mice (n = 10/group) were made hyperthyroid by the application of L-thyroxine (2 µg/ml in drinking water) for 4 weeks. Hypothyroidism was induced in 10-week-old mice by feeding an iodine-free chow supplemented with 0.15% PTU for 4 weeks. We measured mRNA expression levels of Acot8, 11 and 13 in the liver and epididymal and inguinal white and brown adipose tissues (BAT). Furthermore, we investigated hepatic Acot gene expression in TRα- and TRβ-deficient mice. Results: We showed that the expression of Acot8, 11 and 13 is predominantly stimulated by a thyrotoxic state in the epididymal white adipose tissue. In contrast, hypothyroidism predominantly induces the expression of Acot8 in BAT in comparison with BAT of thyrotoxic and euthyroid mice (p < 0.01). However, no significant changes in Acot expression were observed in inguinal white adipose tissue. In liver, Acot gene expression is collectively elicited by a thyrotoxic state. Conclusions: These data suggest that ACOTs are targets of TH and are likely to influence 3,5,3′-triiodo-L-thyronine-orchestrated mechanisms of lipid uptake, storage and utilization to adapt the regulation of metabolic demands.

Thoracic [18F]fluorodeoxyglucose uptake measured by positron emission tomography/computed tomography in pulmonary hypertension.

AbstractPositron emission tomography (PET) visualizes increased cellular [18F]fluorodeoxyglucose ([18F]FDG) uptake. Pulmonary hypertension (PH) is conceived of a proliferative disease of the lung vessels. Increased glucose uptake can be quantified as pulmonary [18F]FDG uptake via PET imaging. Because the angioproliferative mechanisms in PH are still in need of further description, the aim of the present study was to investigate whether [18F]FDG PET/CT imaging can elucidate these pathophysiologic mechanisms in different etiologies of PH.Patients (n = 109) with end-stage pulmonary disease being evaluated for lung transplant were included in this observational study. Mean standardized uptake value (SUVmean) of predefined regions of interest in lung parenchyma (LP), left (LV), and right ventricle (RV) of the heart, and SUVmax in pulmonary artery (PA) were determined and normalized to liver uptake. These SUV ratios (SUVRs) were compared with results from right heart catheterization (mean pulmonary artery pressure [mPAP], pulmonary vascular resistance [PVR]), and serum N-terminal pro-brain natriuretic peptide. Group comparisons were performed and Pearson correlation coefficients (r) were calculated.The [18F]FDG uptake ratios in LP, RV, RV/LV, and PA, but not in LV, were found to be significantly higher in both patients with mPAP ≥25 mm Hg (P = 0.013, P = 0.006, P = 0.049, P = 0.002, P = 0.68, respectively) and with PVR ≥480 dyn·s/cm5 (P < 0.001, P = 0.045, P < 0.001, P < 0.001, P = 0.26, respectively). The [18F]FDG uptake in these regions positively correlated also with mPAP, PVR, and N-terminal pro-brain natriuretic peptide. The SUVR of PA positively correlated with the SUVR of LP and RV (r = 0.55, r = 0.42, respectively).Pulmonary and cardiac [18F]FDG uptake in PET imaging positively correlated with the presence and severity of PH in patients with end-stage pulmonary disease. Increased glucose metabolism in the central PAs seems to play a certain role in terms of severity of PH. These results suggest that [18F]FDG-PET imaging can help understand the pathophysiology of PH as a proliferative pulmonary disease.

Robust, fully automatic delineation of the head contour by stereotactical normalization for attenuation correction according to Chang in dopamine transporter scintigraphy.

AbstractObjectivesChang’s method, the most widely used attenuation correction (AC) in brain single-photon emission computed tomography (SPECT), requires delineation of the outer contour of the head. Manual and automatic threshold-based methods are prone to errors due to variability of tracer uptake in the scalp. The present study proposes a new method for fully automated delineation of the head based on stereotactical normalization. The method was validated for SPECT with I-123-ioflupane.MethodsThe new method was compared to threshold-based delineation in 62 unselected patients who had received I-123-ioflupane SPECT at one of 3 centres. The impact on diagnostic power was tested for semi-quantitative analysis and visual reading of the SPECT images (six independent readers).ResultsThe two delineation methods produced highly consistent semi-quantitative results. This was confirmed by receiver operating characteristic analyses in which the putamen specific-to-background ratio achieved highest area under the curve with negligible effect of the delineation method: 0.935 versus 0.938 for stereotactical normalization and threshold-based delineation, respectively. Visual interpretation of DVR images was also not affected by the delineation method.ConclusionsDelineation of the head contour by stereotactical normalization appears useful for Chang AC in I-123-ioflupane SPECT. It is robust and does not require user interaction.Key Points•Chang attenuation correction in brain SPECT requires delineation of the head contour. •Manual and threshold-based methods are prone to errors. •The study proposes a fully-automated method for delineation based on stereotactical normalization. •The method is shown to work reliably in I-123-ioflupane SPECT. •It might improve the workflow of I-123-ioflupane SPECT in everyday patient care.